API

Relationship: 868

Title

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Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen

Upstream event

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Induction, CYP1A2/CYP1A5

Downstream event

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Oxidation, Uroporphyrinogen

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Aryl hydrocarbon receptor activation leading to uroporphyria adjacent Moderate Low

Taxonomic Applicability

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Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
chicken Gallus gallus High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
Adults High
Juvenile High

Key Event Relationship Description

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The oxidation of uroporphyrinogen to its corresponding porphyrin (UROX) is preferentially catalyzed by the phase one metabolizing enzyme, CYP1A2, in mammals[1][2] and CYP1A5 in birds[3]. Uroporphyrinogen, an intermediate in heme biosynthesis, is normally converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD)[4]; induction of CYP1A2 expression translates to increased protein levels and therefore an increased incidence of binding, and oxidation of uroporphyrinogen, preventing its normally dominant conversion to coproporphyrinogen.

Evidence Supporting this KER

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WOE for this KER is moderate.

Biological Plausibility

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Uroporphyrinogen has clearly been identified as a substrate of CYP1A2/5, which results in its oxidation to uroporphyrin[1][2][3].

Empirical Evidence

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Include consideration of temporal concordance here

UROX activity is increased by inducers of the CYP1A subfamily[4][1] and inhibited by substrates of CYP1A2[2], indicating that uroporphyrinogen binds to the active site of CYP1A2. Furthermore, mice with a higher endogenous level of CYP1A2 are more susceptible to porphyrin accumulation[5] and CYP1A2 knock-out prevents chemical-induced uroporphyria all-together[6][7][8]; therefore, CYP1A2 is essential for UROX. A mild porphyric response was observed in the presence of iron loading and 5-aminolevulinic acid (ALA; a heme precursor) in AHR-/- mice, indicating that CYP1A2 induction is not absolutely necessary, but that constitutive CYP1A2 levels are sufficient for UROX under certain conditions[9].

Uncertainties and Inconsistencies

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It is worth noting that Cyp1a2(-/-) knockout mice have up to 40% of the UROX activity of Cyp1a2(+/+) mice[7], suggesting that some UROX activity is CYP1A2-independent. Likewise, transfection of human Cyp1a1, Cyp3a4, Cyp3a5, or Cyp2e1 in insect cells resulted in UROX activity[10], suggesting that UROX can be catalyzed by other CYPs than CYP1A2 both in mouse and human. Additionally, iron overload or other induced pathways can potentially induce UROX [13]. However, it was shown in mice that only CYP1A2-dependent UROX activity is associated with UROD inhibition[7]. No such experiment was conducted in human, therefore, uncertainties remain for that species. 

In mice, TCDD can elicit AhR-dependent, CYP1A1/A2-independent mitochondrial ROS production suggesting that general oxidative stress induced independently of CYP1A2 induction may contribute to the resulting overall UROX by TCDD [14].  

Phillips et al.[11] were able to generate uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+, which translates into intrinsic iron-overload and reduced UROD activity) to develop porphyria in the absence of external stimuli; CYP1A2 knockout alone prevented porphyrin accumulation, but with the addition of iron and ALA to the triple knockout, modest porphyria was observed. Therefore, under extreme porphyric conditions, UROX leading to porphyria can occur in the absence of the CYP1A2 enzyme.

Altogether, these results indicate that while CYP1A2 is a major catalysis of UROX activity, other CYPs and/or modulating factors are involved in the pathway.

 

Quantitative Understanding of the Linkage

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Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Correlation between total hepatic uroporphyrin accumulation and hepatic CYP1A2 activities in mice after exposure to TCDD (A), 4-PeCDF (B), PCB 126 (C), or PCB 118 (D). (Source: van Birgelen et al. (1996). Toxicol. Appl. Pharmacol. 138 (1), 98-109.)

UROX is positively correlated with CYP1A2/5 activity[12] but this relationship has not been quantitatively describes. It has been noted however, that a CYP1A2 induction of just 2-fold dramatically induces porphyrin accumulation in iron-loaded mice[5].

Response-response Relationship

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Time-scale

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Known modulating factors

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Iron

Iron status can profoundly modify the level of uroporphyrin accumulation especially in mice. In fact iron overload alone of mice will eventually produce a strong hepatic uroporphyria which is markedly genetically determined and toxicity can be ameliorated by chelators [15-16]. In human suffering from uroporphyrin accumulation, it was found that lowering body iron stores by bleeding or now chelators causes remission [17].

Cycling between the ferrous (Fe2+) and ferric (Fe3+) redox states allows Fe to catalyze the Haber-Weiss reaction, in which highly reactive OH is generated from H2O2 and O2•−. Thus, by catalyzing the formation of reactive oxygen species, it is suggested that iron can increase the rate at which uroporphyrinogen is oxidized to uroporphyrin and therefore enhance uroporphyrin formation [18].

 

Ascorbic acid

Ascorbic acid (AA) can prevent uroporphyrin accumulation experimental uroporphyria, but only when hepatic iron stores are normal or mildly elevated [19]. It was shown in chick embryo liver cells that AA could prevent uroporphyrin accumulation caused by treatment with 3,3',4,4'-tetrachlorobiphenyl and 5-aminole-vulinate by competitively inhibiting microsomal CYP1A2-catalyzed oxidation of uroporphyrinogen[20]. Oppositely, in a spontaneous mutant rat that requires dietary AA, hepatic uroporphyrin accumulation caused by treatment with 3-methylcholanthrene or hexachlorobenzene was found to be enhanced when the animals were maintained on a very low AA dietary intake[21].

 

Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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CYP1A2 catalyzes UROX in mice, rats and humans[1][2][11], as does CYP1A5 in chickens[3] .

References

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  1. 1.0 1.1 1.2 1.3 Jacobs, J. M., Sinclair, P. R., Bement, W. J., Lambrecht, R. W., Sinclair, J. F., and Goldstein, J. A. (1989). Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem. J 258 (1), 247-253.
  2. 2.0 2.1 2.2 2.3 Lambrecht, R. W., Sinclair, P. R., Gorman, N., and Sinclair, J. F. (1992). Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch. Biochem. Biophys. 294 (2), 504-510.
  3. 3.0 3.1 3.2 Sinclair, P. R., Gorman, N., Walton, H. S., Sinclair, J. F., Lee, C. A., and Rifkind, A. B. (1997). Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab. Dispos. 25 (7), 779-783.
  4. 4.0 4.1 Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
  5. 5.0 5.1 Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002). Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35 (4), 912-921.
  6. Greaves, P., Clothier, B., Davies, R., Higginson, F. M., Edwards, R. E., Dalton, T. P., Nebert, D. W., and Smith, A. G. (2005) Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse. Biochem. Biophys. Res. Commun. 331 (1), 147-152.
  7. Sinclair, P. R., Gorman, N., Dalton, T., Walton, H. S., Bement, W. J., Sinclair, J. F., Smith, A. G., and Nebert, D. W. (1998) Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Biochem. J. 330 ( Pt 1), 149-153.
  8. Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001) Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173 (2), 89-98.
  9. Davies, R., Clothier, B., Robinson, S. W., Edwards, R. E., Greaves, P., Luo, J., Gant, T. W., Chernova, T., and Smith, A. G. (2008) Essential role of the AH receptor in the dysfunction of heme metabolism induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chem. Res. Toxicol. 21 (2), 330-340.
  10. Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S., and Sinclair, J. F. (1998b). Uroporphyrinogen oxidation catalyzed by human cytochromes P450. Drug Metab Dispos. 26 (10), 1019-1025.
  11. 11.0 11.1 11.2 Phillips, J. D., Kushner, J. P., Bergonia, H. A., and Franklin, M. R. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol. Dis. 47 (4), 249-254.
  12. van Birgelen, A. P., DeVito, M. J., Akins, J. M., Ross, D. G., Diliberto, J. J., and Birnbaum, L. S. (1996). Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls derived from hepatic porphyrin accumulation in mice. Toxicol. Appl. Pharmacol. 138 (1), 98-109.
  13. Caballes F.R., Sendi, H., and Bonkovsky, H. L. (2012). Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 32 (6), 880-893.
  14. Senft, A.P., Dalton, T.P., Nebert, D.W., Genter, M.B., Puga, A., Hutchinson, R.J., Kerzee, J.K., Uno, S., and Shertzer, H.G. (2002). Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radic Biol Med 33, 1268-1278.

  15. Smith, A. G., & Francis, J. E. (1993). Genetic variation of iron-induced uroporphyria in mice. Biochemical Journal291 (1), 29.
  16. Gorman, N., Zaharia, A., Trask, H. S., Szakacs, J. G., Jacobs, N. J., Jacobs, J. M., Sinclair, P. R. (2007). Effect of an oral iron chelator or iron‐deficient diets on uroporphyria in a murine model of porphyria cutanea tarda. Hepatology46 (6), 1927-1834.
  17. Ippen H. (1977). Treatment of porphyria cutanea tarda by phlebotomy. Semin Hematol.14, 253-9.
  18. Fader, K. A., Nault, R., Kirby, M. P., Markous, G., Matthews, J., & Zacharewski, T. R. (2017). Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity. Toxicology and applied pharmacology321, 1-17.
  19. Gorman, N., Zaharia, A., Trask, H. S., Szakacs, J. G., Jacobs, N. J., Jacobs, J. M., ... & Sinclair, P. R. (2007). Effect of iron and ascorbate on uroporphyria in ascorbate‐requiring mice as a model for porphyria cutanea tarda. Hepatology, 45 (1), 187-194.
  20. Sinclair PR, Gorman N, Walton HS, Bement WJ, Jacobs JM, Sinclair JF. (1993). Ascorbic acid inhibition of cytochrome P450-catalyzed uroporphyrin accumulation. Arch Biochem Biophys. 304, 464-470.
  21. Sinclair PR, Gorman N, Sinclair JF, Walton HS, Bement WJ, Lambrecht RW. (1995). Ascorbic acid inhibits chemically induced uroporphyria in ascorbate-requiring rats. Hepatology. 22, 565-572.